Akira Kamiya

Microbial contamination of antiseptics and disinfectants

BACKGROUNDnThere have been a number of reports on microbial contamination of antiseptics and disinfectants. At present, however, the necessity of measures to prevent contamination do not seem to be fully appreciated. We investigated microbial contamination of antiseptics and disinfectants that are used in our hospital.nnnMETHODSnFifty-one samples of benzalkonium chloride and chlorhexidine gluconate that were being used in the hospital were examined. Viability of the contaminants detected in these samples was also tested in the agents. Then we examined measures to prevent contamination of these agents.nnnRESULTSnMicrobial contamination was detected at 10(2) to 10(7) CFU/ml in the following samples: 6 of 23 samples of cotton balls soaked in 0.02% benzalkonium chloride kept in a canister for antisepsis and disinfection (26.1%); 7 of 13 samples of 0.02%, benzalkonium chloride or 0.02% chlorhexidine gluconate in an irrigation apparatus kept at 37 degrees C for vaginal douching (53.8%); and 9 of 15 samples of 0.02% benzalkonium chloride or 0.05% chlorhexidine gluconate for storage of suction catheters in a plastic bottle (60%). The major contaminants were Burkholderia cepacia, Pseudomonas aeruginosa, Xanthomonas maltophilia, and Pseudomonas fluorescens. The first two organisms examined grew in the agents. After improvements in the handling of the antiseptics and disinfectants, no microbial contamination was observed.nnnCONCLUSIONSnIt is necessary to check microbial contamination of diluted benzalkonium chloride and diluted chlorhexidine gluconate that are in use. Such products are not recommended as antiseptics.

Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: A randomized controlled trial

Objectives Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events. Methods We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90u200ammHg) with calcium channel blocker (CCB) benidipine 4u200amg/day were randomly assigned to receive angiotensin receptor blocker (ARB), &bgr;-blocker, or thiazide diuretic in addition to benidipine. Results Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-&bgr;-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-&bgr;-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (Pu200a=u200a0.3505) and 1.54 in the benidipine-&bgr;-blocker (Pu200a=u200a0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (Pu200a=u200a0.0109) and benidipine and ARB significantly reduced new-onset diabetes (Pu200a=u200a0.0240) compared with benidipine and &bgr;-blocker. All trial treatments were safe and well tolerated. Conclusion CCB combined with ARB, &bgr;-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial: Rationale and design

A number of major clinical trials have demonstrated the clinical benefits of lowering blood pressure and have indicated that a majority of patients with hypertension will require more than one drug to achieve optimal blood pressure control. However, there is little data showing which antihypertensive combination best protects patients from cardiovascular events and which best achieves the target blood pressure with the fewest adverse events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial is the first large-scale investigator-initiated multicenter study with a prospective, randomized, open, blinded endpoint evaluation (PROBE) design to directly compare cardiovascular mortality and morbidity, incidence of adverse drug reaction, and degree of blood pressure reduction in Japanese hypertensive patients for a combination of angiotensin receptor blockers, β-blockers or thiazide diuretics in addition to a calcium antagonist, benidipine hydrochloride, with a response-dependent dose titration scheme. The COPE trial is being conducted with the cooperation of more than 100 centers and clinics in Japan and involves 3,000 patients, who will be followed for 3 years. Eligible patients are being enrolled from May 2003 until May 2006. Results from the COPE trial should provide new evidence for selecting optimal combination therapies for hypertensive patients.

A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome

BackgroundTo evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34xa0kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor–II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.MethodsEighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5xa0mg, 1.0xa0mg or 3.0xa0mg each of the peptides was mixed with incomplete Freund’s adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of “the cocktail of 5 peptides” on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4xa0weeks.ResultsThe vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of “peptides cocktail” did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7xa0months. The median overall survival time (MST) was 13.5xa0months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8xa0months) than those with poorer immune responses (MST; 3.7xa0months) (pu2009=u20090.032).ConclusionOur cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.Clinical trial registrationUMIN-CTR number UMIN000004948.

Microbial contamination of dialysate and its prevention in haemodialysis units.

At the haemodialysis centres of nine hospitals in Japan, microbial contamination of treated water (reverse osmosis method), acid and bicarbonate concentrates, and dialysate was investigated. Among these fluids used in haemodialysis, the dialysate was most frequently contaminated and had the highest concentration of bacteria. Of 40 dialysate samples analysed, 42.5% showed a bacterial count of more than 2000cfu/mL, which was above the Association for the Advancement of Medical Instrumentation (AAMI) standard. However, among the 40 samples from 20 dialysis machines, all six dialysate samples from three dialysis machines that used an ultrafiltration membrane in the circuit before the entrance of the dialysate into the dialyser, showed a bacterial count of < or =10 cfu/mL. In addition, when an ultrafiltration membrane was used in the circuit before the entrance of the dialysate into the dialyser for four dialysis machines showing dialysate samples contaminated with 10(4)-10(5)cfu/mL the bacterial count in dialysate samples from these machines became zero. Because dialysis machines are susceptible to microbial contamination, it is necessary to take measures such as placing an ultrafiltration membrane into the circuit before the entrance of dialysate into the dialyser.

Microbial contamination of 'sterile water' used in Japanese hospitals.

We examined the following samples of water from 10 hospitals for microbial contamination: water obtained using an ultra filtration system (UF water), a reverse osmosis system (RO water), a water distillation system (distilled water) and tap water. UF water and RO water are used for handwashing before surgery, and distilled water for the preparation of drugs. All 10 samples of tap water examined were contaminated with < 10 colony forming units (cfu)/mL. Thirteen (68%) of 19 samples of UF water, nine (53%) of 17 samples of RO water and 15 (79%) of 19 samples of distilled water were contaminated with 10(1)-10(4) cfu/mL. The majority of micro-organisms were non-fermentative bacteria such as Sphingomonas paucimobilis and CDC gr. IV C-2. Japanese hospitals commonly use UF water and RO water for preoperative handwashing under the assumption that it is sterile. Our results suggest, however, that these types of water are inferior microbiologically to tap water. Distilled water from the dispensary was also contaminated with micro-organisms. The available chlorine content of tap water was 0.17-0.42 ppm and that of UF water (from tap water) 0-0.06 ppm. There was no available chlorine in RO water or distilled water (each from tap water). The reduction or disappearance of available chlorine appears to be associated with microbial contamination of UF water, RO water and distilled water.

A phase ΙI study of five peptides combination with oxaliplatin-based chemotherapy as a first-line therapy for advanced colorectal cancer (FXV study).

BackgroundWe previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.MethodsThe primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3xa0mg each) mixed with 1.5xa0ml of IFA which was subcutaneously administered weekly for the first 12xa0weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.ResultsBetween February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (pu2009=u20090.910). The median OS was 20.7xa0months in the HLA-A*2402-matched group and 24.0xa0months in the unmatched group (log-rank, pu2009=u20090.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) ofu2009<u20093.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, pu2009=u20090.289) but showed a delayed response.ConclusionsAlthough no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR ofu2009<u20093.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registrationTrial registration: UMIN000001791.

Combination therapy for hypertension in the elderly: a sub-analysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) Trial.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90u2009mmu2009Hg). We further evaluated the efficacy and safety of these combination therapies in older (⩾65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (1533⩾65 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08–6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03–5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.

Microbial contamination of enteral feeding solution and its prevention

In an investigation of microbial contamination of enteral feeding solutions, all 22 residual solutions obtained immediately after administration were contaminated at concentrations of 10(3) to 10(6) viable counts/ml. Major contaminants were glucose-nonfermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter calcoaceticus var anitratus. Contamination seemed to have been caused by frequent reuse of bag-type containers and the infusion tubes connected to the bags, neither of which can be washed or dried. Decontamination methods were evaluated by using polypropylene containers that can be washed and disinfected for administration. Few Serratia marcescens on the inside wall of the container were removed by rinsing with tap water, alone or in combination with detergent scrub. Tap water and detergent plus air-drying at 56 degrees C for 1 hour reduced Serratia marcescens only somewhat. Tap water and detergent plus immersion in 0.01% sodium hypochlorite for 1 hour or in water at 70 degrees C for 3 minutes eliminated all 10(11) cells of Serratia marcescens.

Efficacy of substance P and insulin-like growth factor-1 peptides for preventing postsurgical superficial punctate keratopathy in diabetic patients

PurposeThe efficacy of eyedrops containing peptides based on substance P (FGLM-amide) and insulinlike growth factor-1 (SSSR) for prevention of superficial punctate keratopathy (SPK) after cataract surgery in individuals with type 2 diabetes was examined.MethodsTwenty-nine patients (29 eyes) with diabetes were enrolled in a double-masked, prospective, randomized, placebo-controlled clinical study. They were randomly assigned to one of two groups that received eyedrops containing either FGLM-amide and SSSR (n = 14) or phosphate-buffered saline (n = 15) four times a day for 14 days starting 1 day after phacoemulsification. SPK scores (area, density, and combined area and density) were determined before as well as 1, 3, 7, and 14 days after surgery as main outcome measures.ResultsSPK scores did not differ between the two groups before surgery or before initiation of treatment. At day 2 after treatment initiation, all SPK scores were significantly lower in the FGLM-amide/SSSR group than in the control group. The density score was also significantly lower in the former group at day 7 after surgery. All scores returned to preoperative levels by day 14 after surgery in both groups.ConclusionsEyedrops containing FGLM-amide and SSSR were effective for the prevention of SPK after cataract surgery in diabetic patients.